INTRODUCTION: It is well known that platelets from diabetic patients can be resistant to clinically used antiplatelet drugs. METHODS: To assess the phenomenon in more detail, 50 adult patients suffering from type 1 diabetes mellitus (T1D) were recruited and their responses to 7 platelet aggregation inducers, as well as to 3 clinically used antiplatelet drugs (acetylsalicylic acid /ASA/, ticagrelor and vorapaxar) and one experimental compound, 4-methylcatechol, were assessed ex vivo. A control group of 50 generally healthy age-matched controls was also included for comparison. RESULTS: T1D patients exhibited a lower aggregation reaction to 3 inducers but were conversely more resistant to the effect of ASA and vorapaxar than controls. Ticagrelor tended to be less active in T1D as well. On the other hand, 4-methylcatechol was equally or even more potent in T1D than in healthy controls. Plasma glucose levels above 7 mM were associated with lower platelet aggregation responses to four aggregation inducers. In contrast, the effect of 4-methylcatechol, unlike that of ASA, did not appear to be strongly influenced by glycemia. Further subanalyses, excluding hypertensive patients and significantly more frequently administered drugs, did not substantially modify the results. CONCLUSION: Conclusively, 4-methylcatechol seems to be a prototypical antiplatelet compound with a strong effect even in diabetic patients.

• Keywords
• 4-methylcatechol, Aggregation, Diabetes mellitus, Platelets,
• MeSH
• Platelet Aggregation * drug effects   MeSH
• Aspirin * therapeutic use   pharmacology   adverse effects   MeSH
• Diabetes Mellitus, Type 1 * blood   diagnosis   drug therapy   MeSH
• Adult MeSH
• Platelet Aggregation Inhibitors * therapeutic use   adverse effects   pharmacology   MeSH
• Catechols * therapeutic use   pharmacology   MeSH
• Blood Glucose metabolism   drug effects   MeSH
• Lactones * therapeutic use   pharmacology   MeSH
• Drug Resistance MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Pyridines * therapeutic use   pharmacology   MeSH
• Case-Control Studies MeSH
• Ticagrelor therapeutic use   MeSH
• Blood Platelets * drug effects   metabolism   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Aspirin * MeSH
• Platelet Aggregation Inhibitors * MeSH
• Catechols * MeSH
• Blood Glucose MeSH
• Lactones * MeSH
• Pyridines * MeSH
• Ticagrelor MeSH
• vorapaxar MeSH Browser

Chelation is the rational treatment modality in metal overload conditions, but chelators are often non-selective and can, hence, cause an imbalance in the homeostasis of physiological metals including calcium and magnesium. The aim of this study was to develop an affordable, rapid but sensitive and precise method for determining the degree of chelation of calcium and magnesium ions and to employ this method for comparison on a panel of known metal chelators. Spectrophotometric method using o-cresolphthalein complexone (o-CC) was developed and its biological relevance was confirmed in human platelets by impedance aggregometry. The lowest detectable concentration of calcium and magnesium ions by o-CC was 2.5 μM and 2 μM, respectively. The indicator was stable for at least 110 days. Four and seven out of twenty-one chelators strongly chelated calcium and magnesium ions, respectively. Importantly, the chelation effect of clinically used chelators was not negligible. Structure-activity relationships for eight quinolin-8-ols showed improvements in chelation particularly in the cases of dihalogen substitution, and a negative linear relationship between pKa and magnesium chelation was observed. Calcium chelation led to inhibition of platelet aggregation in concentrations corresponding to the complex formation. A novel method for screening of efficacy and safety of calcium and magnesium ion chelation was developed and validated.

• Keywords
• Chelator, Depletion, Methodology, Platelet, Selectivity,
• MeSH
• Platelet Aggregation drug effects   MeSH
• Chelating Agents * chemistry   MeSH
• Magnesium * chemistry   MeSH
• Humans MeSH
• Drug Evaluation, Preclinical methods   MeSH
• Blood Platelets drug effects   metabolism   MeSH
• Calcium * analysis   metabolism   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Chelating Agents * MeSH
• Magnesium * MeSH
• Calcium * MeSH

BACKGROUND AND AIMS: It is well known that elevated cholesterol is associated with enhanced platelet aggregation and patients suffering from familial hypercholesterolemia (FH) have a high risk of thrombotic cardiovascular events. Although decreasing cholesterol level is associated with attenuation of platelet hyperactivity, there are currently no data on the effect of convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) on platelet reactivity in FH. The aim of the study was to analyse the impact of different therapies including PCSK9ab on platelet aggregation in FH. METHODS: This study enrolled all 15 patients treated in the University Hospital Hradec Králové for FH. PCSK9ab have been administered in 12 of 15 patients while 8 patients were also undergoing lipid apheresis. Blood samples from all patients including pre- and post-apheresis period were tested for platelet aggregation triggered by 7 inducers, and the effect of 3 clinically used drugs (acetylsalicylic acid, ticagrelor and vorapaxar) was compared as well. RESULTS: Although apheresis decreased the reactivity of platelets in general, platelet responses were not different between non-apheresis patients treated with PCSK9ab and apheresis patients (post-apheresis values) with the exception of ristocetin. However, when compared to age-matched healthy population, FH patients had significantly lower platelet aggregation responses to 4 out of 7 used inducers and higher profit from 2 out of 3 used antiplatelet drugs even after exclusion of FH patients regularly receiving conventional antiplatelet treatment. CONCLUSION: This study showed for the first time the suitability of PCSK9ab treatment for reduction of platelet reactivity in FH patients.

• Keywords
• ADP receptor, Acetylsalicylic acid, Antiplatelet, Dyslipidemia, Ticagrelor, Vorapaxar,
• MeSH
• Platelet Aggregation * drug effects   MeSH
• Adult MeSH
• Hyperlipoproteinemia Type II * blood   therapy   drug therapy   MeSH
• Platelet Aggregation Inhibitors * therapeutic use   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Antibodies, Monoclonal therapeutic use   pharmacology   MeSH
• PCSK9 Inhibitors * MeSH
• Proprotein Convertase 9 * immunology   MeSH
• Aged MeSH
• Blood Component Removal * MeSH
• Blood Platelets drug effects   metabolism   immunology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Platelet Aggregation Inhibitors * MeSH
• Antibodies, Monoclonal MeSH
• PCSK9 Inhibitors * MeSH
• PCSK9 protein, human MeSH Browser
• Proprotein Convertase 9 * MeSH

Elevated low-density lipoprotein (LDL) cholesterol levels lead to atherosclerosis and platelet hyperaggregability, both of which are known culprits of arterial thrombosis. Normalization of LDL cholesterol in familial hypercholesterolemia (FH) is not an easy task and frequently requires specific treatment, such as regularly performed lipid apheresis and/or novel drugs such as proprotein convertase subtilisin kexin 9 monoclonal antibodies (PCSK9Ab). Moreover, a high resistance rate to the first-line antiplatelet drug acetylsalicylic acid (ASA) stimulated research of novel antiplatelet drugs. 4-methylcatechol (4-MC), a known metabolite of several dietary flavonoids, may be a suitable candidate. The aim of this study was to analyse the antiplatelet effect of 4-MC in FH patients and to compare its impact on two FH treatment modalities via whole-blood impedance aggregometry. When compared to age-matched, generally healthy controls, the antiplatelet effect of 4-MC against collagen-induced aggregation was higher in FH patients. Apheresis itself improved the effect of 4-MC on platelet aggregation and blood from patients treated with this procedure and pretreated with 4-MC had lower platelet aggregability when compared to those solely treated with PCKS9Ab. Although this study had some inherent limitations, e.g., a low number of patients and possible impact of administered drugs, it confirmed the suitability of 4-MC as a promising antiplatelet agent and also demonstrated the effect of 4-MC in patients with a genetic metabolic disease for the first time.

• Keywords
• 4-methylcathechol, familial hypercholesterolemia, lipid apheresis, platelet,
• MeSH
• Hyperlipoproteinemia Type II * drug therapy   MeSH
• Cholesterol, LDL MeSH
• Humans MeSH
• Antibodies, Monoclonal pharmacology   therapeutic use   MeSH
• Proprotein Convertase 9 MeSH
• Proprotein Convertases therapeutic use   MeSH
• Blood Component Removal * methods   MeSH
• Subtilisin MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-methylcatechol MeSH Browser
• Cholesterol, LDL MeSH
• Antibodies, Monoclonal MeSH
• Proprotein Convertase 9 MeSH
• Proprotein Convertases MeSH
• Subtilisin MeSH